DESCRIPTION

BILTRICIDE® (praziquantel) is a trematodicide provided in tablet form for
the oral treatment of schistosome infections and infections due to liver fluke.

BILTRICIDE (praziquantel) is 2-(cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4H-pyrazino
[2, 1-a] isoquinolin-4-one with the molecular formula; C19H24N2O2.
The structural formula is as follows:

Praziquantel is a white to nearly white crystalline powder of bitter taste.
The compound is stable under normal conditions and melts at 136-140°C with
decomposition. The active substance is hygroscopic. Praziquantel is easily soluble
in chloroform and dimethylsulfoxide, soluble in ethanol and very slightly soluble
in water.

INDICATIONS

BILTRICIDE (praziquantel) is indicated for the treatment of infections due to: all species
of schistosoma (for example, Schistosoma mekongi, Schistosoma japonicum,
Schistosoma mansoni and Schistosoma hematobium), and infections due
to the liver flukes, Clonorchis sinensis/Opisthorchis viverrini (approval of
this indication was based on studies in which the two species were not differentiated).

DOSAGE AND ADMINISTRATION

The dosage recommended for the treatment of schistosomiasis is: 20 mg/kg bodyweight
three times a day as a one day treatment, at intervals of not less than 4 hours
and not more than 6 hours. The recommended dose for clonorchiasis and opisthorchiasis
is: 25 mg/kg bodyweight three times a day as a one day treatment, at intervals
of not less than 4 hours and not more than 6 hours. The tablets should be washed
down unchewed with water during meals. Keeping the tablets or segments thereof
in the mouth can reveal a bitter taste which can promote gagging or vomiting.

HOW SUPPLIED

BILTRICIDE (praziquantel) is supplied as a 600 mg white to orange tinged, film-coated, oblong
tablet with three scores. The tablet is coded with “BAYER” on one
side and “LG” on the reverse side. When broken, each of the four
segments contains 150 mg of active ingredient so that the dosage can be easily
adjusted to the patient's bodyweight.

Segments are broken off by pressing the score (notch) with thumbnails. If ¼
of a tablet is required, this is best achieved by breaking the segment from
the outer end.

SIDE EFFECTS

Adverse Events

In general BILTRICIDE (praziquantel) is very well tolerated. Side effects are usually mild
and transient and do not require treatment. The following side effects were
observed generally in order of severity: malaise, headache, dizziness, abdominal
discomfort with or without nausea, rise in temperature and, rarely, urticaria.
Such symptoms can, however, also result from the infection itself. Such side
effects may be more frequent and/or serious in patients with a heavy worm burden.

DRUG INTERACTIONS

Concomitant administration of rifampin, a strong P450 inducer, with praziquantel
is contraindicated and must be avoided (see CONTRAINDICATIONS). In a
crossover study with a 2-week washout period, 10 healthy subjects ingested a
single 40 mg/kg dose of praziquantel following pre-treatment with oral rifampin
(600 mg daily for 5 days). Plasma praziquantel concentrations were undetectable
in 7 out of 10 subjects. When a single 40 mg/kg dose of praziquantel was administered
to these healthy subjects two weeks after discontinuation of rifampin, the mean
praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel
was given alone. In patients receiving rifampin, for example, as part of a combination regimen for the treatment of tuberculosis, alternative agents for schistosomiasis
should be considered. However, if treatment with praziquantel is necessary,
treatment with rifampin should be discontinued 4 weeks before administration
of praziquantel. Treatment with rifampin can then be restarted one day after
completion of praziquantel treatment.

Chloroquine, when taken simultaneously, may lead to lower concentrations of
praziquantel in blood. The mechanism of this drug-drug interaction is unclear.

Grapefruit juice was reported to produce a 1.6-fold increase in the Cmax and
a 1.9-fold increase in the AUC of praziquantel. However, the effect of this
exposure increase on the therapeutic effect and safety of praziquantel has not
been systematically evaluated.

WARNINGS

Therapeutically effective levels of BILTRICIDE (praziquantel) may not be achieved when administered
concomitantly with strong P450 inducers, such as rifampin (see CONTRAINDICATIONS).

PRECAUTIONS

General

Approximately 80% of a dose of praziquantel is excreted in the kidneys, almost
exclusively ( > 99%) in the form of metabolites. Excretion might be delayed
in patients with impaired renal function, but accumulation of unchanged drug
would not be expected. Therefore, dose adjustment for renal impairment is not
considered necessary. Nephrotoxic effects of praziquantel or its metabolites
are not known.

Caution should be exercised in the administration of the usual recommended
dose of praziquantel to hepatosplenic schistosomiasis patients with moderate
to severe liver impairment (Child-Pugh class B and C). Reduced metabolism of
praziquantel by the liver in these patients may lead to considerably higher
and longer lasting plasma concentrations of unmetabolized praziquantel (See
CLINICAL PHARMACOLOGY/Special Populations).

Minimal increases in liver enzymes have been reported in some patients.

Patients suffering from cardiac irregularities should be monitored during treatment.

As BILTRICIDE (praziquantel) can exacerbate central nervous system pathology due to schistosomiasis,
as a general rule this drug should not be administered to individuals reporting
a history of epilepsy and/or other signs of potential central nervous systems
involvement such as subcutaneous nodules suggestive of cysticercosis.

When schistosomiasis or fluke infection is found to be associated with cerebral
cysticercosis it is advised to hospitalize the patient for the duration of treatment.

Mutagenesis, Carcinogenesis

Mutagenic effects in Salmonella tests found by one laboratory have not been
confirmed in the same tested strain by other laboratories. Long term carcinogenicity
studies in rats and golden hamsters did not reveal any carcinogenic effect.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to
40 times the human dose and have revealed no evidence of impaired fertility
or harm to the fetus due to praziquantel. There are, however, no adequate and
well-controlled studies in pregnant women. An increase of the abortion rate
was found in rats at three times the single human therapeutic dose. While animal
reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.

Nursing mothers

Praziquantel appeared in the milk of nursing women at a concentration of about
1/4 that of maternal serum although it is not known whether a pharmacological
effect is likely to occur in children. Women should not nurse on the day of
BILTRICIDE (praziquantel) treatment and during the subsequent 72 hours.

Pediatric use

Safety in children under 4 years of age has not been established.

Geriatric use

Clinical studies of praziquantel did not include a sufficient number of subjects
ages 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences
in responses between the elderly and younger patients, but greater sensitivity
of some older patients cannot be ruled out.

This drug is known to be substantially excreted by the kidney. Because elderly
patients are more likely to have decreased renal function, the risk of toxic
reactions to this drug may be greater in these patients.

OVERDOSE

In rats and mice the acute LD50 was about 2,500 mg/kg. No data are available
in humans. In the event of overdose a fast-acting laxative should be given.

CONTRAINDICATIONS

BILTRICIDE (praziquantel) is contraindicated in patients who previously have shown hypersensitivity
to the drug or any of the excipients. Since parasite destruction within the
eye may cause irreversible lesions, ocular cysticercosis must not be treated
with this compound.

Concomitant administration with strong Cytochrome P450 (P450) inducers, such
as rifampin, is contraindicated since therapeutically effective blood levels
of praziquantel may not be achieved (see PRECAUTIONS: DRUG INTERACTIONS).
In patients receiving rifampin who need immediate treatment for schistosomiasis,
alternative agents for schistosomiasis should be considered. However, if treatment
with praziquantel is necessary, rifampin should be discontinued 4 weeks before
administration of praziquantel. Treatment with rifampin can then be restarted
one day after completion of praziquantel treatment (see PRECAUTIONS: DRUG
INTERACTIONS).

CLINICAL PHARMACOLOGY

Praziquantel induces a rapid contraction of schistosomes by a specific effect
on the permeability of the cell membrane. The drug further causes vacuolization
and disintegration of the schistosome tegument.

After oral administration BILTRICIDE (praziquantel) is rapidly absorbed (80%), subjected to
a first pass effect, metabolized and eliminated by the kidneys. Maximal serum
concentration is achieved 1-3 hours after dosing. The half-life of praziquantel
in serum is 0.8-1.5 hours.

Special Populations

The pharmacokinetics of praziquantel were studied in 40 patients with Schistosoma
mansoni infections with varying degrees of hepatic dysfunction (See table 1).
In patients with schistosomiasis, the pharmacokinetic parameters did not differ
significantly between those with normal hepatic function (Group 1) and those
with mild (Child-Pugh class A) hepatic impairment. However, in patients with
moderate-to-severe hepatic dysfunction (Child-Pugh class B and C), praziquantel
half-life, Cmax, and AUC increased progressively with the degree of hepatic
impairment. In Child-Pugh class B, the increases in mean half-life, Cmax, and
AUC relative to Group 1 were 1.58-fold, 1.76-fold, and 3.55-fold, respectively.
The corresponding increases in Child-Pugh class C patients were 2.82-fold, 4.29-fold,
and 15-fold for half-life, Cmax, and AUC.

Table 1: Pharmacokinetic parameters of praziquantel in four
groups of patients with varying degrees of liver function following administration
of 40 mg/kg under fasting conditions.